Approximately 5% of the U.S. population suffers from Non-Insulin Dependent Diabetes Mellitus (NIDDM) or Type II diabetes. Abnormalities of plasma lipid and lioprotein concentrations (referred to as dyslipidemia) occur commonly in Type II diabetics. Dyslipidemia is a major risk factor in the development of cardiovascular disease and markedly reduces the quality of life and shortens the lifespan of many diabetic individuals. The broad, long-range objective of this project is to develop novel and proprietary tocotrienols as drugs for the treatment of diabetic dyslipidemia. The initial strategy to meet this objective includes conducting experiments in a predictive animal disease model to determine the impact of a novel tocotrienol on disease severity and progression. Once the potential of this tocotrienol test compound has been established, additional tocotrienols will be similarly synthesized and tested. Ultimately, the goal of this program is to select one or more lead candidates for development under an FDA-cleared IND program. The research plan for Phase I consists of (i) administering a proprietary tocotrienol to an experimental disease model, (ii) determining its bioavailability following oral administration at different dose levels, (iii) determining its impact of on circulating levels of lipids, glucose and low density lipoproteins and (iv) performing preliminary studies to evaluate product safety through gross and microscopic examination of major organs. The research under Phase II will focus on expansion of the structural class of candidate tocotrienol compounds and in-vivo evaluation of these additional compounds. The most promising candidate(s) emerging from Phase III will be selected for clinical development in Phase III. It is anticipated that once safety and efficacy has been established, the clinical development compounds will be licensed to a major pharmaceutical firm for continued development and eventual marketing. PROPOSED COMMERCIAL APPLICATIONS: The pharmaceutical industry continues to seek improved therapeutic agents for treating diabetic dyslipidemia. The tocotrienol to be used in this study is one of a patented class of compounds that has shown initial promise in the treatment of dyslipidemia. The research proposed in this application will evaluate the potential application of this class of proprietary compounds as new therapeutic agents for treating diabetic dyslipidemia.